The three major human apolipoprotein (apo) E isoforms are encoded by distinct alleles (E2, e3, and c4). Compared with c2 and F3, F4 increases the risk of cognitive impairments and of developing Alzheimer's disease (AD). ApoE4 interacts with female gender, resulting in an even greater risk of developing AD. Understanding apoE-gender interactions is important for developing AD treatments. To assess how interactions between gender and apoE isoforms affect cognition, we study transgenic mice expressing human apoE isoforms in the brain and lacking mouse apoE (apoe-/-). As they age, female, but not male, apoE4 mice develop progressive impairments in spatial learning and memory in the water maze, compared with age- and sex-matched wild-type, apoe-/- or apoE3 mice. This could be relevant to cognitive impairments in human 4 carriers. Spatial memory is impaired in AD. Because the cognitive impairments are observed in female apoE4 mice that express apoE4 in neurons or astrocytes, they are independent of the cellular source of apoE. Adult female mice that express both apoE3 and apoB4 do not show cognitive deficits in the water maze, indicating that apoE3 antagonizes the effects of apoE4 on cognition. We hypothesize that sex steroids contribute to the gender-dependent behavioral alterations in apoE4 mice and that androgens antagonize the apoE4-induced behavioral alterations. Our preliminary data show that testosterone and dihydrotestosterone antagonize the memory retention deficits of adult apoE4 female mice in the water maze. We further hypothesize that androgen receptors (ARs) mediate protection against apoE4-induced cognitive impairments. ApoE4 male mice, which do not show cognitive deficits in the water maze, developed cognitive impairments after blockade of androgen receptors, whereas apoE3 male mice did not. The Specific Aims are: (1) To determine whether apoE4 has gender-specific effects on performance in hippocampus dependent tests and whether sex steroids contribute to these effects; (2) To determine whether ARs protect against apoE4-induced cognitive impairments; (3) To determine whether gender- and isoform-specific effects of apoE on AR function in the hippocampus contribute to cognitive impairments; and (4) To determine whether apoE3 antagonizes the effects of apoE4 on cognitive function. The proposed study will help to elucidate the roles of apoE isoforms in the brain and their interactions with sex steroids in cognition. This is important for our understanding of cognitive function in health as well as in diseases characterized by cognitive impairments and will likely advance the development of therapeutic intervention to prevent or even reverse cognitive impairments.